Erythropoietin (Epo) is the principal hematopoietic growth factor that promotes the viability, differentiation and proliferation of mammalian erythroid progenitor cells (S. Krantz, Blood 77, 419–34 (1991)). The biologic effects of Epo are mediated via its interaction with its specific transmembrane receptor, EpoR (H. Youssoufian, Blood 81, 2223–36 (1993)). The EpoR lacks intrinsic tyrosine kinase activity and upon ligand binding activates a receptor-associated tyrosine kinase Jak2 which is critical for anti-apoptosis and mitogenic signaling via the EpoR (O. Miura et al., Blood 84, 1501–7 (1994); B. Witthuhn et al., Cell 74, 227–36 (1993); J. Ihle, Nature 337, 591–4 (1995); H. Zhuang et al., J Biol. Chem. 270, 14500–4 (1995)). Activated Jak2 then phosphorylates a number of cytoplasmic proteins as well as the EpoR itself. Expression of Epo receptors has been reported on several non-hematopoietic cell types including vascular endothelial cells, placental tissue, neuronal cells, kidney and cardiomyocytes (A. Anagnostou et al., Proc. Natl. Acad. Sci. USA 91, 3974–8 (1994); S. Masuda et al., J. Biol. Chem. 268, 112–8–16 (1993); S. Sawyer et al., Blood74, 103–9 (1989); M. Wald et al., J. Ce. Physiol. 167, 461–8 (1996)).
Recombinant human Epo (r-HuEpo) has been widely used in many different types of cancers for the treatment or prevention of chemo-radiotherapy induced anemia (A. Moliterno and J. Spivak, Hematol. Oncol. Clin. North Am. 10, 345–63 (1996)). For instance, in patients with breast cancer, r-HuEpo has been investigated in clinical trials for its potential beneficial effects in the prevention or treatment of chemotherapy or radiation therapy-related anemia (L. Del Mastro et al., J. Clin. Oncol. 15, 2715–21 (1997); H. Ludwig et al., Ann. Oncol. 4, 161–7 (1993); P. Sweeney et al., Br. J. Cancer 77, 1996–2002 (1998); S. Vijayakumar et al., Int. J. Radiat. Oncol. Biol. Phys 26, 721–9 (1993)), for mobilization of peripheral blood progenitor cells (C. Waller et al., Bone Marrow Transplant 24, 19–24 (1999)), to increase the rate of hematopoietic recovery following high dose chemotherapy (P. Benedetti Panici et al., Br. J. Cancer 75, 1205–12 (1997); S. Filip et al., Neoplasma 46, 166–72 (1999)) as well as use in ex vivo expansion strategies of stem cells (C. Bachier et al., Exp Hematol. 27, 615–23 (1999); L. Pierelli et al., Exp. Hematol. 27, 416–24 (1999); P. Stiff et al., Blood 95, 2169–74 (2000); W. Vogel et al., Blood 86, 1362–7 (1996)). Similarly, r-HuEpo has been investigated in several clinical trials of squamous cell cancers of head-neck (F. Dunphy et al., Cancer 86, 1362–7 (1999); M. Henke et al., radiother Oncol 50, 185–90 (1999); G. Mantovani et al., Oncol. Rep. 6, 421–6 (1999)) and uterine cervix (K. Dusenbery et al., Int. J. Radiat. Oncol. Biol. Phys. 29, 1079–84 (1994)).
In view of the foregoing, it would be extremely desirable to understand the association of Epo with tumor growth and how EpoR may be involved in cancer pathophysiology and progression.